Stabilized solutions of ergot alkaloidal salts



UNITED STABILIZED SOLUTIONS @F ERGQI! ALKAILUIDAL SALTS Clair S. Dyas, Pearl River, N. ii astlg'nor to.

Lederle Laboratories, line, New York, N. W, acorporation of Delaware No Drawing. Application May I, 19%,

Serial No. 533,665

' '1 Glaims. (on. 167-6?) This invention relates to stable solutions of of extracting the ergot alkaloids, I have found water-soluble,organic acid salts of ergot alkaloids that a convenient method of doing so is as foland to a method oi preparing the same. I lows. g

The alkaloids of ergot have been known to The crude ergot is finely ground, preferably to possess oxytocic activity, and both the total alkaa particle size which will pass through a 20-mesh loids and certain specific ones found therein have sieve. The finely-ground drug is extracted with been used at the-time of parturition in both hupetroleum benzin, gasoline, or similar fat solvent mans and animals. The proper dosage is imporby a method of percolation until only a trace of tant, as too little is of practically no value, and oil remains in the percolate. The fat solvent may too much causes violentor prolonged contraction .10 be recovered by distillation and re-used, while of the uterus, either of which is both undesirable the oily residue is suitable for use in the menuand dangerous. Accordingly, the activity of the facture of soap and its by-produ'ct, glycerin. After preparation must be determined and standardized extraction of the'oil, the drug is allowed to dry.

in order that a proper therapeutic dosage of the The dried drug is mixed with ammonia drug can be administered. water, using 50% by volume of the original weight It is also generally known that aqueous soluof the drug. Solutions of other, alkaline matetions of the various ergot alkaloidal salts tend rials may be used in place of ammonia water in to deteriorate, particularly when exposed to the this step. While the drug may be mixed with action of light and oxygen. This deterioration is the ammonia by any suitable means, I prefer to indicated by a gradual darkening of the soluuse a power mixer so that all portions of the drug tion and the formation of aprecipitate. Attempts are thoroughly moistened, thus assuring a comhave been made to stabilize these preparations, plete extraction of the therapeutic alkaloids. The but for some reason or another the salts of ergot moist dru is transferred to bags and allowed to alkaloids fail to respond to the usual anti-oxidant swell for about two hours, after which it is transstabllizers. One method of avoiding the deteri- 26 ferred to a suitable closed percolator and covered oration of the alkaloidal salts is to isolate them with purified benzene. While benzene is the sol-- in crystalline form and seal the preparation in vent of choice, other water-immiscible solvents an atmosphere of nitrogen or carbon dioxide. may be used, which include ethyl ether, chloro- When the seal is broken, the gas escapes; the form, and the like.

remaining material then deteriorates and soon be- 30 The crude drug is allowed to remain in contact comesof little value. with the benzene for a period of from about 12 One of the objects of my invention is, therefore hours to about 18 hours, after which the benzene to prepare a solution of salts of ergot alkaloids is drawn ofi. The benzene extract is agitated which will retain practically its full therapeutic slowly for from about 3 hours to about 6 hours activity over a long period of time. It is a further with a quantity of a solution (containing 1% of object of my invention to obtain a stable aqueous alpha-hydroxy isobutyric acid, of thiourea. ergot alkaloid preparation which can be stored and distilled water to make 100%) equal to about for some tim after its preparation and then used A; to about A the volume of the benzene extract.

for oral or parenteral administration without the In place of alpha-hydroxy isobutyric acid I may necessity of re-assaying the solution or otherwise 40 use other organic acids, such as acetic, succinic, treating it. Other objects of my invention will lactic, tartaric, glutaric, glutamic. aspartic, etc. appear hereinafter. The use of inorganic acids is avoided since they In accordance with my invention I have disfrequently cause the precipitation of partially incovered that aqueous solutions of salts of ergot soluble alkaloidal salts of the mineral acid. Prefalkaloids can be stabilized by the addition thereto erably, the aqueous solution has a pH within the of small amounts of thiourea. In general, such range 2 to 6 obtained by the use of weak organic stable solutions of the ergot alkaloids maybe acids. While the above represents the preferred prepared by extracting crude ergot with a fat proportions of thiourea and acid, in carrying out solvent, treating the defatted ergot with an alkamy invention I may use from about /2% to 3% line solution, then extracting the ergot alkaloids of acid with from about to 1% of thiourea.

with a water-immiscible solvent and thereafter The acid solution is separated from the waterextracting the alkaloids from the solvent with immiscible solvent and subjected to vacuo withan aqueous solution containing-thiourea. and havout heat to remove the last traces of solvent.

ing a pH of from about 2.0 to 6.0. While I do High temperatures and exposure to light and air not wish to limit myself to any particular method should be avoided throughout the preparation.

asoasvs enough new solvent added to 'cover it. The so vent-acid extraction is continued until the drug is exhausted. Each acid extraction is assayed, and those meeting the requirements are mixed, while the final extractions, being below standard, are set aside to be used on subsequent lots of I drug in the place of new acid solution.

A bacterlostatic preservative, such as chlorbu- I tanol mm. per cc.) is added to the assayed stable ergot alkaloid solution. and it is filtered i do not deteriorate noticeably upon storage for periods of several months.

While I have shown above that thiourea can be used to stabilize aqueous acidic extracts of salts of the total alkaloids oi ergot, it is to be understood that thiourea may be used to stabilize thealkaloidal salts of any aqueous extract containing either some or all oi the alkaloidal salts oi ergot. r

The use of thiourea is also advantageous in that it has been shown that small amounts of this substance may be injected into humans or animals without danger.

I claim:

1. A stable therapeutically active aqueous so-' lution of ergot alkaloids which comprises water, water-soluble organic acid salts of the alkaloids of ergot, and thiourea.

2. A stable therapeutically active aqueous solution of ergot alkaloids which comprises water.

water-soluble organic acid salts of the alkaloids oi ergot, and thiourea, said solution having a pH of from about 2.0 to 6,0.

3. A stable therapeutically active aqueous solution of ergot alkaloids which-comprises water, water-soluble alpha-hydroxy isobutyric acid salts of the alkaloids of ergot, and thiourea, said solution having a pH from about 2.0 to 6.0.

4. A stable therapeutically active aqueous solution of ergot alkaloidsrwhich comprises water, water-soluble glutaric acid salts of the alkaloids oi ergot, and thiourea, said solution having a pH from about 2.0 to 6.0.

5. A stable therapeutically active aqueous solution of ergot alkaloids which comprises water,

' water-soluble organic acid salts of the alkaloids of ergot, to 1% of thiourea, and /z% to 3% of alpha-hydroxy isobutyric acid.

6. In the process of producing a stable therapeutically active aqueous solution of ergot alkaloidal salts the step which comprises extracting a water-immiscible solution of ergot alkaloids with an aqueous solution having a pH of from about 2.0 to 6.0 containing thiourea and a weak organic acid.

7; In the process of producing a stable therapeutically active aqueous solution of ergot alkaloidal salts the step which comprises extracting a benzene ergot alkaloid solution with'an aqueous solution containing .to 1% of thiourea and /i.% to 3% of alpha-hydroxy isobutyric acid.

CLAIR s. DYAS. 

